Everolimus for advanced pancreatic neuroendocrine tumors

James C. Yao, Manisha H. Shah, Tetsuhide Ito, Catherine Lombard Bohas, Edward M. Wolin, Eric Van Cutsem, Timothy J. Hobday, Takuji Okusaka, Jaume Capdevila, Elisabeth G E De Vries, Paola Tomassetti, Marianne E. Pavel, Sakina Hoosen, Tomas Haas, Jeremie Lincy, David Lebwohl, Kjell Öberg

Research output: Contribution to journalArticle

1719 Citations (Scopus)

Abstract

BACKGROUND: Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study. METHODS: We randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus. RESULTS: The median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks). CONCLUSIONS: Everolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. (Funded by Novartis Oncology; RADIANT-3 ClinicalTrials.gov number, NCT00510068.)

Original languageEnglish (US)
Pages (from-to)514-523
Number of pages10
JournalNew England Journal of Medicine
Volume364
Issue number6
DOIs
StatePublished - Feb 10 2011
Externally publishedYes

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Neuroendocrine Tumors
Placebos
Disease-Free Survival
Confidence Intervals
Everolimus
Stomatitis
Intention to Treat Analysis
Sirolimus
Exanthema
Drug-Related Side Effects and Adverse Reactions
Hyperglycemia
Fatigue
Disease Progression
Anemia
Cause of Death
Diarrhea

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Yao, J. C., Shah, M. H., Ito, T., Bohas, C. L., Wolin, E. M., Van Cutsem, E., ... Öberg, K. (2011). Everolimus for advanced pancreatic neuroendocrine tumors. New England Journal of Medicine, 364(6), 514-523. https://doi.org/10.1056/NEJMoa1009290

Everolimus for advanced pancreatic neuroendocrine tumors. / Yao, James C.; Shah, Manisha H.; Ito, Tetsuhide; Bohas, Catherine Lombard; Wolin, Edward M.; Van Cutsem, Eric; Hobday, Timothy J.; Okusaka, Takuji; Capdevila, Jaume; De Vries, Elisabeth G E; Tomassetti, Paola; Pavel, Marianne E.; Hoosen, Sakina; Haas, Tomas; Lincy, Jeremie; Lebwohl, David; Öberg, Kjell.

In: New England Journal of Medicine, Vol. 364, No. 6, 10.02.2011, p. 514-523.

Research output: Contribution to journalArticle

Yao, JC, Shah, MH, Ito, T, Bohas, CL, Wolin, EM, Van Cutsem, E, Hobday, TJ, Okusaka, T, Capdevila, J, De Vries, EGE, Tomassetti, P, Pavel, ME, Hoosen, S, Haas, T, Lincy, J, Lebwohl, D & Öberg, K 2011, 'Everolimus for advanced pancreatic neuroendocrine tumors', New England Journal of Medicine, vol. 364, no. 6, pp. 514-523. https://doi.org/10.1056/NEJMoa1009290
Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E et al. Everolimus for advanced pancreatic neuroendocrine tumors. New England Journal of Medicine. 2011 Feb 10;364(6):514-523. https://doi.org/10.1056/NEJMoa1009290
Yao, James C. ; Shah, Manisha H. ; Ito, Tetsuhide ; Bohas, Catherine Lombard ; Wolin, Edward M. ; Van Cutsem, Eric ; Hobday, Timothy J. ; Okusaka, Takuji ; Capdevila, Jaume ; De Vries, Elisabeth G E ; Tomassetti, Paola ; Pavel, Marianne E. ; Hoosen, Sakina ; Haas, Tomas ; Lincy, Jeremie ; Lebwohl, David ; Öberg, Kjell. / Everolimus for advanced pancreatic neuroendocrine tumors. In: New England Journal of Medicine. 2011 ; Vol. 364, No. 6. pp. 514-523.
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T1 - Everolimus for advanced pancreatic neuroendocrine tumors

AU - Yao, James C.

AU - Shah, Manisha H.

AU - Ito, Tetsuhide

AU - Bohas, Catherine Lombard

AU - Wolin, Edward M.

AU - Van Cutsem, Eric

AU - Hobday, Timothy J.

AU - Okusaka, Takuji

AU - Capdevila, Jaume

AU - De Vries, Elisabeth G E

AU - Tomassetti, Paola

AU - Pavel, Marianne E.

AU - Hoosen, Sakina

AU - Haas, Tomas

AU - Lincy, Jeremie

AU - Lebwohl, David

AU - Öberg, Kjell

PY - 2011/2/10

Y1 - 2011/2/10

N2 - BACKGROUND: Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study. METHODS: We randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus. RESULTS: The median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks). CONCLUSIONS: Everolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. (Funded by Novartis Oncology; RADIANT-3 ClinicalTrials.gov number, NCT00510068.)

AB - BACKGROUND: Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study. METHODS: We randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus. RESULTS: The median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks). CONCLUSIONS: Everolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. (Funded by Novartis Oncology; RADIANT-3 ClinicalTrials.gov number, NCT00510068.)

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